Abstract 1226: Targeting BTK family in ER+ breast cancer with Ibrutinib for personalized precision medicine: a double-edged sword

Abstract

Abstract Background: Metastasis is the principal cause of morbidity and mortality from breast cancer. Although current therapies are effective in early-stage of breast cancer, resistance to therapy is common leading to the development of metastasis. The commonest site of metastases is the regional lymph nodes. The presence and the number of involved lymph nodes remains the single best predictor of metastases and an important guide for the use of systemic adjuvant therapy. Identification of the underlying molecular targets of lymph node metastasis and a better understanding how to therapeutically target these will be a significant step in the goal of prevention of metastases. Experimental Design: To determine the key players associated with the development of metastasis in breast cancer, we performed RNA sequencing (Illumina Paired-end RNA-seq) analysis in a cohort of matched pairs of primary and (nodal) metastatic tumors (n=18). Gene expression profiles were analyzed using DESeq2. For targeted therapeutics, we performed orthotopic tumor implantation into mammary fad pads of athymic nude mice of breast cancer models. Results: Our results identified significant differential expression of the Bruton's tyrosine kinase (BTK) family members in nodal metastasis. Among the family members, BTK, BLK, RLK/TXK and JAK3 are expressed at very high levels in the metastatic lesions as compared to matched primary tumors. Among the 51 breast cancer cell lines analyzed, the BTK genes were significantly upregulated in luminal, but not basal cell lines. Categorized by the molecular subtypes of breast cancer, hormone receptor- positive (HR) and /or HER2 overexpressing breast cancer cell lines present higher BTK expression. Among the 51 breast cancer cell lines analyzed, the BTK genes were significantly regulated in both ER+ HER2- (T47D and ZR75.1) and ER+HER2+ (BT-474 and ZR75.30) breast cancer cell lines. Ibrutinib, a selective and irreversible inhibitor of BTK targeting the cysteine-481 residue in the active site, exhibited potent activity in preclinical models of BTK-expressing targets. Ibrutinib decreased primary tumor growth significantly in ER+HER2+ (BT-474) mouse xenograft model in a dose dependent manner (10 mg/kg vs 25 mg/kg; P< 0.05), whereas it promoted the tumor growth in a significant manner in ER+HER2- xenograft models (T47D and ZR75.1; P<0.05). The differences might be due to the differences in model systems due to the HER2 presence. Conclusion: Our data suggests that differential expression of target genes can be used to select agents as treating breast cancer. However, caution is necessary, as, in some situations, this might lead to enhancement of the growth in in vivo in subsets of breast cancer. Citation Format: Yesim Gökmen-Polar, Xiaoping Gu, Edyta Vieth, Sunil Badve. Targeting BTK family in ER+ breast cancer with Ibrutinib for personalized precision medicine: a double-edged sword [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1226. doi:10.1158/1538-7445.AM2017-1226